Some phospholipids from natural sources are known to produce beneficial effects on various conditions in mammals. For example, phospholipids derived from hen egg yolk have been studied as potentially having therapeutic benefits. Natural hen egg yolk extracts are rich in a variety of bioactive phospholipids (BAP). When enriched to 30% with the N-acyl ether-phosphatidylethanolamine (NAEPE) 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine, hen egg yolk extracts have been reported to have anti-cancer properties, including significantly interfering with tumor progression in in vivo chick models. See, Karafiát V., et al., Folia Biologica (Praha) 60, 220-227 (2014). This is consistent with earlier reports that 1-O-octadecyl/hexadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine isolated from ischemic chicken embryos and/or made semisynthetically restricts growth of subcutaneous transplanted sarcomas in mice. See, Kara, J. et al., Neoplasma 33, 187-205 (1986) and Kara J. et al., Neoplasma 40 213-217 (1993).
It is generally believed that the alkyl-ether moiety in NAEPE is necessary for cytotoxic activity because ether-linked lipids are not catabolized in tumors and can accumulate and interfere with vital pathways of the cell. See, Kara, J. et al, Neoplasma 33, 187-205 (1986), Berdel, W. et al., Cancer Res. 43, 541 (1983), and Modolell, M., et al., Cancer Res., 39 4681 (1979).
Unlike classical DNA-targeted cytotoxic agents, alkylphospholipids or BAP may target cellular and intracellular membranes. See Kuerschner, D., et al., PLOS One 7, e31342 (2012). When administered in therapeutic doses, alkylphospholipids may inhibit phosphatidylcholine biosynthesis, interfere with lipid transduction pathways, block the endoplasmic reticular transport, and interfere with the membrane lipid raft function. See, e.g., Blitterswijk. W., et al., Biochim. Biophys. Acta. 1831, 663-674 (2013). Lipid rafts are specialized plasma membrane microdomains having concentrations of cholesterol and sphingomyelins which spatially organize signaling pathways and regulate cell proliferation and apoptosis. See, e.g., van der Luit, A., et al., Mol. Cancer Ther. 6, 2337-2345 (2007). Lipid rafts are more abundant in cancer cells relative to normal cells and have been proposed to serve as entry points for cytotoxic agents into the cells. See, e.g., Li, Y., et al., Am. J. Pathol. 168, 1107-1118 (2006).
In addition to potential anti-neoplastic properties, it has also been reported that ischemic chick embryonic tissue extract enriched to 30% 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)ethanolamine shows significant anti-inflammatory and immunomodulatory effects. See, Vicenova, M. et al., Complementary and Alternative Medicine 14 339 (2014). In in vivo studies of bacterially induced acute pneumonia it was demonstrated that BAP mixtures enriched with NAEPE had a positive effect on disease progression by lowering levels of IL-113, IL-8 in sera and lowering white blood count, as well as reducing lung parenchyma. In vitro studies on the transcriptional activity of proinflammatory cytokine genes related to the activation of intracellular signaling pathways associated with inflammation showed the ability of certain BAP mixtures to influence the immune response of macrophages. Id. Moreover, the NAEPE enriched egg yolk extracts have activities which inhibit the phosphorylation of protein kinase C epsilon. Id.
It is an object of the present invention to identify biologically active lipids, including phosphatidylcholine (PC) and/or sphingomyelin (SPH) and/or lysophosphatidylcholine (LPC) compounds, and mixtures thereof, possessing therapeutic properties, including antiproliferative or antineoplastic properties. Moreover, it is an object of the invention to provide compositions and methods of using these compositions to treat proliferative diseases, including cancer.